Previous studies suggested that the alpha-Calmodulin Kinase II (a-CaMKII) plays a critical role in hippocampal synaptic plasticity and in hippocampal-dependent learning and memory (L&M). Recent work from our laboratory also indicates that this kinase is required for memory consolidation in neocortical sites. These L&M studies, however, were limited by the fact that a-CaMKII was deleted in many brain regions. Using newly developed techniques, we have now derived mutant lines to generate sub-region (CA1, CA3 and dentate gyrus) and cell-type (excitatory neurons) restricted deletions of this kinase. Additionally, we have also used Cre -recombinase in Herpes Simplex Viral (HSV) vectors to specifically manipulate genes in a regional-specific manner. With these unique tools we plan to determine the role of this kinase in hippocampal pre- and post-synaptic plasticity, in learning and in memory consolidation. The specific aims of this proposal are: 1- To determine the role of a-CaMKII in either CAl, CA3 or dentate gyrus in learning and memory. Various models suggest specific roles for each hippocampal sub-region in L&M. We will use mice with post-natal and region restricted null mutations of a-CaMKII to test the role of this kinase in four forms of hippocampal-dependent learning: spatial learning in the Morris water maze, working memory in the 8-arm maze, contextual discrimination with fear conditioning, and social recognition. 2 - To test the role of pre- and post-synaptic a-CaMKII on the induction of long-term potentiation (LTP) in CAl, CA3 and dentate gymus. We will test the pre and post-synaptic role of this kinase in synaptic plasticity not only in CA1, but also in CA3 and dentate gyrus. These studies will also be essential to interpret the behavioral analysis of the mutant lines proposed in Specific Aim #1. 3 - To test the hypothesis that a-CaMKII-dependent plasticity in the hippocampus is critical for early stages of memory consolidation, but that later stages of consolidation require a-CaMKII-dependent plasticity in cortical sites. Recent findings in our laboratory suggest that a-CaMKII is critical for LTP and for memory consolidation in the neocortex. To directly test this hypothesis, we will use cortical and hippocampal transgenic and viral manipulations of a-CaMKII function. The studies proposed here will not only further our understanding of the role of a-CaMKII in synaptic plasticity and in L&M, but they will also be critical for insights into cognitive deficits, such as those associated with aging.